(optionally 17-alkylated) 3alpha-oxygenated 1alpha-sulfonated 5alpha-androstan-17beta-ols and esters thereof



United States Patent (OPTIONALLY 17-ALKYLATED) 3ot-0XYGENATEDIa-SULFONATED Sa-ANDROSTAN-IZB-OLS AND ESTERS THEREOF Paul D. Klimstra,Northbrook, Ill., assignor to G. D. Searle & Co., Chicago, Ill., acorporation of Delaware No Drawing. Filed Nov. 26, 1965, Ser. No.510,036

6 Claims. (Cl. 260397.4)

The present invention is concerned with novel steroidal derivativescharacterized by a la-sulfo substituent and, more particularly, with(optionally 17-alkylated) 3- oxygenated lot-sulfonated5a-androstan-17B-ols and esters corresponding which are represented bythe following structural. formula 5.03M (:\OH:; s:

wherein R is hydrogen or a lower alkanoyl radical, X is hydrogen or alower alkyl radical, Z is a carbonyl or fl-hydroxymethylene radical andM is hydrogen or a metallic cation.

The lower alkyl radicals represented in the foregoing structural formulaare exemplified by methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,and the branchedchain groups isomeric therewith.

wherein R and X are as above defined. The reaction of those startingmaterials with a metallic bisulfite or metabisulfite thus affords thecorresponding la-sulfonated derivative as the sulfonate salt. As aspecific example, 17;9-hydroxy-17a-methyl-5a-androst-l-en 3 one inethanol is heated with an aqueous solution of sodium bisulfite, thusproducing sodium 17fl-hydroxy-17a-methyl-1a-sulfo-5aandrostan-B-one.

The sulfonate salts of the present invention are alternatively producedby reaction of a sulfonate salt, produced as described above, with aninorganic salt or base containing the desired cation. Reaction of theaforementioned sodium 17,8hydroxy-17a-methyl-la-suIfO-Sa-androstan-3-one with calcium oxide thusproduces the corresponding calcium salt.

Reaction of the instant sulfonates salts with a mineral acid affords thecorresponding free sulfonic acid. When sodium 173-hydroxy-Not-methyl-1u-sulfo-5a-androstan-3- one is contacted withsulfuric acid, there is accordingly produced17p-hydroxy-17x-rnethyl-la-sulfo-5a-androstan- 3-one.

The -hydroxy compounds of this invention are conveniently produced byreduction of the corresponding 3- keto derivatives. Reaction of 173-hydroxy-17a-methyl 1asulfo-5a-androstan-3-one with lithium tri-(tertiary-butoxy) aluminum hydride in tetrahydrofuran thus affords17amethyl-la-sulfo-5wandrostane-3,8,17/3-diol.

An alternate procedure for manufacture of the instant l7-(lower-alkanoyl)oxy compounds involves esten'fication of the corresponding17-hydroxy substances. As a specific example,17/3-hydroxy-1a-sulfo-5a-androstan-3-one is contacted with aceticanhydride and pyridine to afford 17/3-acetoxy-lu-sulfo-5a-androstan-3-one.

The compounds of this invention display valuable pharmacologicalproperties. They are hormonal and antihormonal agents, for example, asis evidenced by their anabolic, androgenic and anti-estrogenic activity.They are also inhibitors of the enzymatic action of pepsin. In addition,these compounds are anti-bacterial and antiprotozoal agents inconsequence of their ability to inhibit the growth of such organisms asDiplococcus pneumoniae and Tetrahymena gelleii.

The invention will appear more fully from the examples which follow.These examples are given by way of illustration only and are not to beconstrued as limiting the invention either in spirit or in scope as manymodifications both in materials and methods will be apparent from thisdisclosure to those skilled in the art. In these examples temperaturesare given in degrees centigrade C.) and quantities of materials in partsby weight unless otherwise noted.

Example 1 To a refluxing solution of 5 parts of17B-hydr0xy-l7umethyl-5u-anrdost-l-en-3one in 48 parts of ethanol isadded, with stirring over a period of about minutes, a solution of 1.75parts of sodium bisulfite in 25 parts of water. Refluxing of the mixtureis continued for about 90 minutes longer, and the organic solvent isremoved by distillation under reduced pressure. Addition of methanol tothe resulting aqueous solution results in precipitation of a finelydivided solid, which is collected by filtration, then washedsuccessively with ethanol and dry ether to afford the crude product.That material is purified by recrystallization from methanol-acetone toafford sodium 17 3 hydroxy methyl-1oz sulfo-5u-androstan-3-one, meltingat about l96. This compound is represented by the following structuralformula When an equivalent quantity of17a-ethyl-17fi-hydroxy-5u-androst-1-en-3-one is substituted in theprocedure of Example 1, there is produced sodium 17u-ethyl-17,8-hydroxy-1a-sulfo-5ot-androstan-3-one.

Example 3 To a refluxing solution of 14.4 parts of l7 3-hydroxy-5:androst-l-en-3-one in 144 parts of ethanol is added, dropwise over aperiod of about 1 hours, a solution of 5.2 parts of sodium bisulfite in75 parts of water. The

resulting reaction mixture is heated at the reflux temperature for about2 hours longer, then is distilled under reduced pressure in order toremove the organic solvent. Dilution of the resulting aqueous solutionwith approximately 400 parts of acetone results in precipitation of thecrude product, which is isolated by filtration, then washed successivelywith acetone and hexane and dried under reduced pressure.Recrystallization of that material from aqueous methanol afiords puresodium 175- hydroxy-1a-sulfo-5a-androstan-3-one, melting at about216-219 and exhibiting an optical rotation of +655".

Example 4 A mixture of one part of sodium17/3-hydroxy-l7amethyl-1a-sulfo-5a-androstan-3-one with 36 parts oftetrahydrofuran is heated to effect solution, then is cooled to -5". Tothat mixture is then added a solution of 3 parts of lithiumtri-(tertiary-butoxy) aluminum hydride in 18 parts of tetrahydroturan,and the resulting reaction mixture is stirred for about one hour, thenis poured into a mixture of ice and water containing approximately 35parts by volume of acetic acid. The resulting acidic mixture is allowedto stand at room temperature for about 16 hours, then is concentrated todryness under reduced pressure. The resulting gummy white material isdissolved in hot methanol, then is neutralized by the addition of 10%aqueous sodium hydroxide. The insoluble salts are removed by filtration,and the filtrate is evaporated to dryness under reduced pressure. Theresidue thus obtained is slurried with warm water, and that slurry isneutralized by the addition of hydrochloric acid. The precipitate thusformed is isolated by filtration and dried in air to afford sodium17a-methyl-1a-sulfo-5a-androstane- 313,17fi-diol.

Example 5 When an equivalent quantity of sodium 17a-ethyl-1718-hydroxy-1a-sulfo-Sa-androstan-3-one is substituted in the procedure ofExample '4, there is obtained sodium17aethyl-1a-sulfo-Sa-androstane-3/8,17,8-di0l.

Example 6 The substitution of an equivalent quantity of sodium17fl-hydroxy-1a-sulfo-5a-androstan-3-one in the procedure of Example 4affords sodium la-sulfO-Su-androstane-3,B,17fl-diol. v

Example 7 Example 8 When an equivalent quantity of propionic anhydrideis substituted in the procedure of Example 7, there is produced sodium17fl-propionoxy-1a-sulfo-5a-androstan- 3-one.

Example 9 When an equivalent quantity of sodium 17,8-acetoxy-1a-sulto-5a-androstan-3-one is substituted in the procedure of Example4, there is produced sodium lot-sulfo- 5a-androstane-3fl17/3-diol 17acetate.

Example 10 By substituting an equivalent quantity of sodiumpropionoxy-la-sulfo 5a androstan-3-one and otherwise proceedingaccording to the processes described in Example 4, there is producedsodium la-sulfo-5u-androstane- 35,175-dio1 17-propionate.

What is claimed is:

1. A compound of the formula wherein R is a member of the classconsisting of hydrogen and a lower alkanoyl radical, X is selected fromthe group consisting of hydrogen and a lower alkyl radical and Z is amember of the class consisting of a carbonyl and a fl-hydroxymethyleneradical.

2. As in claim 1, a compound of the formula wherein Z is a member of theclass consisting of a carbonyl and a B-hydroxymethylene radical.

3. As in claim 1, the compound which is sodium 175-hydroxy-l7a-methyl-1a-sulfo-5a-androstan-3-one.

4. As in claim 1, the compound which is sodium 175-hydroxy-1a-sulfo-Sa-androstan-3-one.

5. As in claim 1, the compound which is sodium17amethyl-1a-sulfQ-Su-andmstane,3p,17/3-diol.

6. As in claim 1, the compound which is sodium 175-acetoxy-1u-sulfo-Sa-androstan-3-one.

References Cited UNITED STATES PATENTS 2,567268 9/1951 Beall 260397.42,833,792 5/1958 Dodson 260397.4 2,851,454 9/1958 Pappo et a1 260239.553,118,916 1/1964 Goedicke 260397.4 3,163,578 12/1964 Bruckner et al.l6774 3,252,930 5/1966 Smith et al. 260239.55

LEWIS GOTTS, Primary Examiner.

ELBERT L. ROBERTS, Examiner.

T. MESHBESHER, Assistant Examiner,

1. A COMPOUND OIF THE FORMULA
 3. AS IN CLAIM 1, THE COMPOUND WHICH IS SODIUM 17BHYDROXY-17 A-METHYL-1A-SULFO-5A-ANDROSTAN-3-ONE. 